Determinants of first-line antiretroviral treatment failure among adult patients on treatment in Mettu Karl Specialized Hospital, South West Ethiopia; a case control study

Background Antiretroviral therapy has dramatically reduced Human Immunodeficiency Virus related morbidity and mortality. It has also transformed HIV infection into a manageable chronic condition. However, first-line antiretroviral treatment failure continues to grow especially in resource limited settings. Despite this, determinants of first-line antiretroviral treatment failure are not well studied in Ethiopia. Objective To identify determinants of first-line antiretroviral treatment failure among adult patients on antiretroviral therapy in Mettu Karl Specialized Hospital, South West Ethiopia, in 2020. Methods A hospital based case-control study was conducted from October to November 2020. Simple random sampling technique was used to select participants. Interviewer administered questionnaire and record review were used for data collection. Data were entered into epi data version 3.1 and exported to SPSS version 20 for analysis. Bivariable and multivariable logistic regression analysis were used. At the end, variables with P-value < 0.05 at 95% confidence intervals for adjusted odds ratio were considered statistically significant determinants of first line treatment failure. Result A total of 113 cases and 339 controls were included in the study with response rate of 98.6%. Sixty-four (56.6%) of cases and 183 (54.0%) of controls were females. Baseline WHO clinical stage III and IV (AOR = 1.909, 95% CI: (1.103, 3.305), baseline body mass index<18.5kg/m2(AOR = 2.208,95% CI:(1.257,3.877),baseline CD4 cell count <100cells/mm3 (AOR = 3.016, 95% CI: (1.734, 5.246), having history of TB co-infection (AOR = 1.855, 95% CI: (1.027, 3.353), having history of lost to follow up (AOR = 3.235, 95% CI: (1.096, 9.551), poor adherence to medication (AOR = 7.597, 95% CI: (4.059, 14.219) and initiation of treatment after two years of diagnosis with HIV (AOR = 4.979, 95% CI: (2.039, 12.158) were determinants of first-line antiretroviral treatment failure. Conclusion In this study several variables were found to be determinants of first-line antiretroviral treatment failure. Concerned bodies should give more attention to early diagnosis of HIV, early enrollment in chronic HIV care and early initiation of ART before patients develop advanced WHO clinical stages. In addition, focus has to be given for patients with low CD4 count. Regular screening for TB, counseling on optimal adherence to medication and enhancing nutritional status of patients with low body mass index are also crucial to prevent first-line antiretroviral treatment failure.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.  Methods: A Hospital-based case-control study was conducted from October to November 2020. Simple random sampling technique was used to select participants. Interviewer administered questionnaire and record review were used for data collection. Data were entered into Epi data version 3.1 then exported to SPSS version 20 for analysis. Bivariable and multivariable logistic regression analysis were used. At the end, variables with P value < 0.05 at 95% confidence intervals for adjusted odds ratio were considered statistically significant. Frequent assessment of treatment response is important while the subject is on ART.

Result:
Monitoring the response to ART and diagnosis of treatment failure for patients on antiretroviral therapy is important to achieve treatment goals of ART. First-line antiretroviral treatment failure can be assessed virologically, immunologically and or clinically (5).
WHO recommended viral load testing as the preferred monitoring approach to diagnose and confirm antiretroviral treatment failure in 2013 (7). However, the availability of viral load testing is very limited in low-and middle-income countries, where the majority of people living with HIV reside (8). Viral load provides an early and more accurate indication of treatment failure when compared with clinical and immunological monitoring (4).
Globally, about 10-20% of adult patients on first-line antiretroviral treatment are reported to have developed treatment failure with higher figures (15-25%) being reported in Sub-Saharan Africa (9). In Sub-Saharan Africa, many patients who experience treatment failure do not switch to potent second-line regimens due to resource limitation, yet those who remain on failing first-line regimen experience disproportionately higher morbidity and mortality compared to those who switch (10). In Ethiopia, prevalence of first-line antiretroviral treatment failure was 15.3% by using the three WHO treatment failure criteria (virological, immunological and clinical) (11).
Despite the scaling up of antiretroviral treatment in resource limited settings, development of first-line antiretroviral treatment failure is a big challenge (12). Treatment failure among population taking ART in Ethiopia is a public health concern because patients experiencing treatment failure will have increased risk of morbidity, mortality and increased transmission as well as accumulation of drug resistant mutations (13).
According to a study conducted in the United States(US) in 2014, the cost of treating a patient with a second-line ART drug increases by 24% as compared with the first-line treatment (14). Currently, in Ethiopia where medication is fully funded by the government, treatment failure and frequent substitution of medications are becoming major challenges in control of the disease (15).

Study design, area and period
A Hospital based unmatched case-control study was conducted. The study was conducted at Mettu Karl Specialized Hospital which the only specialized in the area serving a population of more than 1.4 million people with different services including HIV prevention, care and treatment. In this hospital ART service started in 2005. Currently total people receiving ART at the facility is 1600. Mettu Karl Specialized Hospital has laboratory services to determine CD4 count and viral load to monitor ART patients. The study was conducted from October 25 to November 24/2020. Since, poor adherence was found to result in the largest sample size; it was used to determine sample size as independent variable. In previously conducted research proportion of poor adherence was 22.9% in cases and 10.8% in controls (19). By using 5 % margin of error, 80% power, a case to control ratio of 1:3 and using a two population proportion formula, the calculated sample size was 416 (104 cases and 312 controls). Then by adding a 10% nonresponse rate, the final sample size was 458 (115 cases and 343 controls).

Source and Study populations
Simple random sampling technique was used to recruit study subjects for cases and controls.

Data analysis procedures
The collected data was coded and entered into Epi data version 3.1 and exported to statistical  (Table 1).

Bivariable logistic regression analysis of first-line antiretroviral treatment failure
Bivariable logistic regression analysis was carried out to assess the association of variables with first-line treatment failure. Among these variables, smoking, khat chewing, baseline WHO clinical stage, baseline BMI, baseline CD4 count, history of TB co-infection, history of lost to follow up, adherence status to antiretroviral drugs, disclosure status, time lag to initiate ART after diagnosis with HIV were candidates for multivariable logistic regression analysis at P-value <0.25 in bivariable logistic regression model ( Table 2).

Discussion
The identification and management of first-line ART failure is a key challenge for HIV programs in resource-limited settings. Staying on a failing first-line antiretroviral therapy is associated with an increased risk of mortality. In addition to this, development of drug resistance limits the ability to construct new, potent, and tolerable regimens in the future.
This study was aimed to identify determinants of first-line antiretroviral treatment failure.
In this study first-line antiretroviral treatment failure was found to be significantly associated  (28). This might be due to the fact that patients with low body mass index (BMI<18.5kg/m2) have low nutritional status that leads to weakened immunity, blunted immune response and increased risk of first-line antiretroviral treatment failure (29).
The finding of this study indicated that patients with low baseline CD4 count <100cells/mm 3 were three times more likely to fail first-line antiretroviral treatment than patients with baseline CD4 count >=100cells/mm 3  Patients who were enrolled to ART after two years of diagnosis with HIV were nearly five times more likely to develop first-line antiretroviral treatment failure when compared with patients who were enrolled to ART within the same month of being diagnosed with HIV.
This finding was in line with those studies conducted in Zimbabwe (9), in Central Ethiopia St.
Luke Referral Hospital and Tulu bolo General Hospital (36). This might be due to the possibility that patients who stay long time without initiation of ART after diagnosis face an increase in viral load and develop other opportunistic infections. This might also be due to the difficulty of viral suppression and increase CD4 cell count when the patients delay to start ART (41).

Conclusion
This study showed that baseline stage III and IV WHO clinical stage of HIV, low baseline Body Mass Index (<18.5 kg/m 2 ), baseline CD4 count <100cells/mm 3 , having history of TB co-infection, having history of lost to follow up, poor adherence to antiretroviral drugs and initiation of ART after two years of diagnosis with HIV positive were factors associated with first-line antiretroviral treatment failure.